P838: PEGCETACOPLAN RAPIDLY STABILIZES COMPLEMENT INHIBITOR NAÏVE PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA EXPERIENCING HEMOLYSIS WITH ACUTE HEMOGLOBIN DECREASES; PRINCE TRIAL POST HOC ANALYSIS
Authors: R. Wong, M. Al-Adhami, J. Savage, R. Horneff, M. Yeh, T. Dumagay, D. Gomez-Almaguer
Journal: HemaSphere (2022)

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan (PEG) is the first FDA/EMA-approved C3 complement-inhibitor that provides broad hemolysis control in patients with PNH. Aims: This is the first report from the PRINCE trial on the efficacy of PEG in control arm rescue patients using a post hoc time-aligned analysis. Methods: PRINCE is a phase 3, randomized, open-label study, that evaluates the efficacy of PEG in improving lactate dehydrogenase (LDH) and hemoglobin (Hb) levels in patients with PNH. 53 adult (≥18 years old), complement-inhibitor naïve (no prior eculizumab/ravulizumab) patients with LDH ≥1.5x the upper limit of normal (ULN) (≥339 U/L) and Hb below the lower limits of normal (LLN) (males: ≤13.6 g/dL; females: ≤12.0 g/dL), were enrolled. Patients were randomized 2:1 to receive PEG (1080 mg subcutaneously twice weekly, n=35; PEG arm) or to the Control arm (trials were in regions where C5 inhibitors were not available, n=18) for 26 weeks. Patients in the Control arm had the option to escape to PEG treatment (Rescue arm) should they exhibit signs of hemolysis and acute Hb decline by ≥2 g/dL from their baseline. Key endpoints included both changes from baseline in LDH and Hb levels. Because patients could be rescued at any point, a post hoc analysis was performed to time-align the Rescue patients (n=11), based on the start of PEG dosing, with patients in the PEG arm, to compare changes in LDH and Hb levels over time by PEG exposure. Results: 61% (11/18) of Control arm patients experienced acute Hb decreases allowing rescue by PEG treatment. All Rescue patients had a pre-rescue LDH ≥2X ULN (mean 2424.0 U/L) and all had a rapid response to PEG treatment with a significant decrease in LDH level by Week 1 (mean 422.1 U/L) with 5/11 patients achieving ≤1.5X ULN; by Week 2 mean LDH levels were in the normal range (186.6 U/L) with 8 patients below ULN and 2 patients below 1.5X ULN, suggesting complete control of intravascular hemolysis. These results are similar to PEG arm patients (150.4 U/L) (Figure A). Seven of the eleven patients showed a significant increase in Hb level (Week 2 mean Hb for Rescue patients: 10.9 g/dL; PEG patients: 11.19 g/dL); four patients showed no change, potentially due to underlying bone marrow dysfunction (3 had a history of aplastic anemia). Three patients had a transfusion within 5 days of starting PEG treatment; 1 of them remained transfusion dependent after rescue and did not have a Hb change. The time-align plots (Figures A and B) show Rescue patients had rapid improvements in LDH to normal levels and Hb improvements similar to PEG arm patients. PEG demonstrated a favorable risk-benefit profile. No deaths or serious adverse events deemed related to PEG occurred and no drug discontinuations due to PEG-related adverse events were reported. The most common AEs were injection site reaction (PEG [including Rescue patients for all AEs], 30.4%, n=14; Control arm, 0.0%), hypokalemia (PEG, 13.0%, n=6; Control arm, 11.1%, n=2), dizziness (PEG, 10.9%, n=5; Control arm, 0.0%), and fever (PEG, 8.7%, n=4; Control arm, 0.0%). Image:Summary/Conclusion: PEG treatment was able to rapidly stabilize complement-inhibitor naïve patients experiencing acute hemolysis with substantial Hb decrease, and normalize LDH and raise Hb levels. The treatment effect of PEG on both LDH and Hb levels over time was largely similar between the PEG arm patients and Rescue patients. PEG represents a new effective therapeutic option with a favorable safety profile for PNH patients.